CN105503569A - Synthetic method for Netupitant intermediate 2-(3,5-bi-trifluoromethyl-phenyl)-2-methyl-propionic acid - Google Patents
Synthetic method for Netupitant intermediate 2-(3,5-bi-trifluoromethyl-phenyl)-2-methyl-propionic acid Download PDFInfo
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- CN105503569A CN105503569A CN201610013748.4A CN201610013748A CN105503569A CN 105503569 A CN105503569 A CN 105503569A CN 201610013748 A CN201610013748 A CN 201610013748A CN 105503569 A CN105503569 A CN 105503569A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Abstract
The invention discloses a synthetic method for Netupitant intermediate 2-(3,5-bi-trifluoromethyl-phenyl)-2-methyl-propionic acid. The synthetic method includes the steps that a compound 3,5-bi(trifluoromethyl) bromobenzene is used as a raw material and reacts with diethyl malonate in first solvent in the presence of a first alkali reagent to produce a first compound, then the first compound is subjected to saponification and decarboxylic reactions with a second alkali reagent in second solvent to produce a second compound, finally the second compound reacts with a methylation reagent in the presence of a third alkali reagent in third solvent to obtain 2-(3,5-bi-trifluoromethyl-phenyl)-2-methyl-propionic acid. The Netupitant intermediate is prepared through a one-pot method, the used raw materials are easy to obtain and low in cost, and the synthetic method is short in reaction flow path, easy to operate, low in production cost and convenient to apply to industrial production.
Description
Technical field
The present invention relates to a kind of synthesis how appropriate pyrrole smooth (NETUPITANT) intermediate 2-(3,5-two-trifluoromethyl-phenyl) method of-2-rnethyl-propanoic acid, belong to technical field of medicine synthesis.
Background technology
How appropriate pyrrole smooth (NETUPITANT) is one of effective constituent of the compound medicine Akynzeo defending the exploitation of material (Eisai) company, is can the new drug of the effective nausea and vomiting that preventing cancer chemotherapy acute phase and lag period, (starting in chemotherapy 25-120 hour) produced.Its English commodity are called Netupitant, English language Chemical name is called: 2-[3,5-bis (trifluoromethyl) phenyl]-N, 2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl) pyridin-3-yl] propanamide.
Molecular structural formula is as follows:
As one of the effective constituent of compound medicine Akynzeo, Akynzeo's is granted, is the data based on 2 clinical trials, and these researchs relate to the cancer patients that 1720 examples accept chemotherapy.First term research shows, in acute phase (in 24 hours), Akynzeo treatment group has the patient of 98.5% how to vomit without successive or need extra medicine support, and Aloxi treatment group Proportion of patients is 89.7%.In addition, this research also have recorded the ability that 2 kinds of medicines were felt sick with treatment in lag period and the omnidistance prevention of emesis of chemotherapy.Data show, in lag period and chemotherapy whole process, Akynzeo treatment group has the patient of 90.4% and 80.6% respectively without what vomiting successive, and Aloxi treatment group ratio is respectively 80.1% and 76.5%, and result for the treatment of is remarkable.
At present, how the synthetic method of appropriate pyrrole smooth (NETUPITANT) can realize (US8426450B1) according to following reaction scheme:
Can find from said synthesis route, how appropriate pyrrole smooth (NETUPITANT) intermediate 2-(3,5-is two-trifluoromethyl-phenyl) and-2-rnethyl-propanoic acid (hereinafter referred to as chemical compounds I) is the important intermediate of synthesizing how appropriate pyrrole smooth (NETUPITANT), its molecular structural formula is as follows:
How the important intermediate of appropriate pyrrole smooth (NETUPITANT), namely the synthetic method of compound 1 can be prepared by following route:
Existing method synthetic compound 1, need five step reactions, reaction time is long, and uses methyl iodide as methylating reagent, and harmful, expensive, thus this route well can not be applicable to suitability for industrialized production.
Summary of the invention
For solving the deficiencies in the prior art, the object of the present invention is to provide a kind of reactions steps short, process control, aftertreatment is simple, and yield is high, and can the synthetic method of cinacalcet intermediate 3-(3-trifluoromethyl) propyl alcohol of operate continuously.
In order to realize above-mentioned target, the present invention adopts following technical scheme:
How appropriate one pyrrole smooth intermediate 2-(3,5-be two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, comprise the following steps:
，
With such as formula two (trifluoromethyl) bromobenzene of the compound 3.5-shown in II for raw material, deposit at the first alkali reagent and in the first solvent, react 1-24h with diethyl malonate in case, preferred 8-10h, temperature of reaction be 0 DEG C to the first solvent reflux temperature, preferably 90 DEG C, generate such as formula the compound one shown in III, then by compound one in the second solvent, saponification is carried out by the second alkali reagent, decarboxylic reaction 1-24h generates such as formula the compound two shown in IV, preferred 4-6h, temperature of reaction is room temperature to the second solvent reflux temperature, finally compound two is deposited at the 3rd alkali reagent and in the 3rd solvent, react 1-24h with methylating reagent in case, preferred 6-10h, temperature of reaction be-5 DEG C to the 3rd solvent reflux temperature, obtain such as formula the 2-(3 shown in I, 5-pair-trifluoromethyl-phenyl)-2-rnethyl-propanoic acid.
Further, the first above-mentioned alkali reagent is sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, any one in sodium ethylate, preferred sodium hydride.
And the amount of substance of the first above-mentioned alkali reagent and two (trifluoromethyl) bromobenzene of 3.5-is than being (1-2): 1, the amount of preferred substance is than being 1.5:1, and the amount of substance of described diethyl malonate and two (trifluoromethyl) bromobenzene of 3.5-is than being (1-2): 1, the amount of preferred substance is than being 1.3:1.
And the first described solvent is any one in dimethyl sulfoxide (DMSO), DMF, Isosorbide-5-Nitrae-dioxane, toluene, dimethylbenzene, preferred Isosorbide-5-Nitrae-dioxane.
Further, the second above-mentioned alkali reagent is any one in lithium hydroxide, sodium hydroxide, potassium hydroxide, preferred sodium hydroxide, and the second alkali reagent is (1-5) with the amount of substance ratio of compound one: 1, preferred 4.0:1.
And the second described solvent is any one in methylene dichloride, toluene, acetonitrile, water, tetrahydrofuran (THF), methyl alcohol, ethanol, propyl carbinol, particular methanol.
In addition, the 3rd described alkali reagent is sodium hydride, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, any one in sodium ethylate, preferred sodium hydride.
And the 3rd described alkali reagent is (1-4) with the ratio of the amount of substance of compound two: 1, preferred 2.5:1, and described methylating reagent is (1-3.5) with the ratio of the amount of substance of compound two: 1, preferred 1.5:1.
And the 3rd described solvent is any one in dimethyl sulfoxide (DMSO), DMF, Isosorbide-5-Nitrae-dioxane, toluene, dimethylbenzene, acetonitrile, tetrahydrofuran (THF), preferred tetrahydrofuran (THF).
Described methylating reagent is methylcarbonate or methyl-sulfate, preferably sulfuric acid dimethyl ester.
Usefulness of the present invention is: the present invention is by adopting the one kettle way preparation how smooth intermediate of appropriate pyrrole, and not only used raw material is easy to get, with low cost, and reaction process is short, and simple to operate, production cost is low, is convenient to suitability for industrialized production application.
Accompanying drawing explanation
Fig. 1 is the HPLC spectrogram of product of the present invention;
Fig. 2 is the nucleus magnetic hydrogen spectrum figure of product of the present invention.
Embodiment
Below in conjunction with specific embodiment, concrete introduction is done to the present invention.
Embodiment 1
Diethyl malonate (355g, 2.218mol) is added, N in reactor, dinethylformamide 1.5L, ice bath is cooled to 0 DEG C, stirs, adds sodium hydride (102.4g in batches, 2.559mol), finish equality of temperature and stir 1h, in reaction solution, add two (trifluoromethyl) bromobenzene (500g, 1.706mol) of compound 3.5-, be warming up to 90 DEG C, reaction 10h.Cooling, adds 4L water, divides three extractions, anhydrous sodium sulfate drying by 5L ethyl acetate, filters and is spin-dried for and obtains crude product (670.28g), not purifiedly directly carries out next step and reacts.
Under room temperature, in reactor, add crude Compound one (670.3gg, 1.706mol), methyl alcohol 2.5L, sodium hydroxide (272.5g, 6.812mol), stir and be warming up to backflow, reaction 5h.Cooling, be spin-dried for solvent, divide three extractions, anhydrous sodium sulfate drying with ethyl acetate 4L after acid adjustment, be spin-dried for and obtain crude Compound two (523.16g), not purified directly carry out next step react.
Under room temperature, crude Compound two (523.2g is dropped into successively in reaction flask, 1.706mol), N, dinethylformamide 5L,-5 DEG C add sodium hydride (170g in batches, 4.265mol), equality of temperature stirs 1h, drip methyl-sulfate (363.2g, 2.559mol), 50 DEG C of reaction 10h, be cooled to 10 DEG C and drip 4L sodium hydroxide (204.7g, 5.118mol) solution, drip and finish, 50 DEG C of reaction 4h, be cooled to room temperature, pressure reducing and steaming solvent, a large amount of solid is separated out in acid adjustment, filter, white solid 2-(3 is obtained by sherwood oil re-crystallizing in ethyl acetate after drying, 5-pair-trifluoromethyl-phenyl) the total molar yield of-2-rnethyl-propanoic acid 320.2g(three-step reaction: 62.5%).
Embodiment 2
Diethyl malonate (355g, 2.218mol) is added, Isosorbide-5-Nitrae-dioxane 1.5L in reactor.Ice bath is cooled to 0 DEG C, stirs, adds potassium tert.-butoxide (287g, 2.559mol) in batches, finishes equality of temperature and stirs 1h, adds two (trifluoromethyl) bromobenzene (500g, 1.706mol) of compound 3.5-, is warming up to 100 DEG C, reaction 10h to reaction solution.Cooling, adds 4L water, divides three extractions, anhydrous sodium sulfate drying by 5L ethyl acetate, filters and is spin-dried for and obtains crude Compound one (678.54g), not purifiedly directly carries out next step and reacts.
Under room temperature, in reactor, add crude Compound 3(678.5g, 1.706mol), ethanol 3L, sodium hydroxide (272.5g, 6.812mol), stirs the only backflow that heats up, reaction 6h.Be spin-dried for solvent, divide three extractions, anhydrous sodium sulfate drying with ethyl acetate 4L after acid adjustment, be spin-dried for and obtain crude Compound two (516.97g), not purified directly carry out next step reaction.
Under room temperature, crude Compound two (517g is dropped into successively in reaction flask, 1.706mol), tetrahydrofuran (THF) 5L,-5 DEG C add sodium hydrogen (170.6g in batches, 4.265mol), equality of temperature stirs 1h, drip methyl-sulfate (322.7g, 2.559mol), 50 DEG C of reaction 10h, be cooled to 10 DEG C and drip 4L sodium hydroxide (204.7g, 5.118mol) solution, drip and finish, 50 DEG C of reaction 4h, be cooled to room temperature, pressure reducing and steaming solvent, a large amount of solid is separated out in acid adjustment, filter, white solid 2-(3 is obtained by sherwood oil re-crystallizing in ethyl acetate after drying, 5-pair-trifluoromethyl-phenyl)-2-rnethyl-propanoic acid 317.5g, (the total molar yield of three-step reaction is 62.0%).
Embodiment 3
Diethyl malonate (355.2g, 2.218mol) is added, toluene 1.5L in reactor.Ice bath is cooled to 5 DEG C, stirs, adds sodium hydride (102g, 2.559mol) in batches, finishes equality of temperature and stirs 1h, adds two (trifluoromethyl) bromobenzene (500g, 1.706mol) of compound 3.5-, is warming up to 90 DEG C, reaction 10h to reaction solution.Cooling, adds 4L water, separatory, divides three extractions, anhydrous sodium sulfate drying by 5L ethyl acetate, filters and is spin-dried for and obtains crude Compound one (675.51g), not purifiedly directly carries out next step and reacts.
Under room temperature, in reactor, add crude Compound 3(675.6g, 1.706mol), methyl alcohol 2.5L, potassium hydroxide (382.2g, 6.812mol), stirs the only backflow that heats up, reaction 4h.Be spin-dried for solvent, divide three extractions, anhydrous sodium sulfate drying with ethyl acetate 4L after acid adjustment, be spin-dried for and obtain crude Compound two (530.47g), not purified directly carry out next step reaction.
Under room temperature, crude Compound 4(530.5g is dropped into successively in reaction flask, 1.706mol), tetrahydrofuran (THF) 5L,-5 DEG C add sodium hydrogen (170.6g in batches, 4.265mol), equality of temperature stirs 1h, drip methyl-sulfate (322.7g, 2.559mol), 50 DEG C of reaction 10h, be cooled to 10 DEG C and drip 4L sodium hydroxide (204.7g, 5.118mol) solution, drip and finish, 50 DEG C of reaction 4h, be cooled to room temperature, pressure reducing and steaming solvent, a large amount of solid is separated out in acid adjustment, filter, white solid 2-(3 is obtained by sherwood oil re-crystallizing in ethyl acetate after drying, 5-is two-trifluoromethyl-phenyl) the total molar yield of-2-rnethyl-propanoic acid 325.1g(three-step reaction is 63.5%).
Fig. 1 is the HPLC spectrogram of product of the present invention; Fig. 2 is the nucleus magnetic hydrogen spectrum figure of product of the present invention.
-2-rnethyl-propanoic acid as depicted in figs. 1 and 2: products therefrom of the present invention is 2-(3,5-pair-trifluoromethyl-phenyl), and purity is greater than 99.5%.
More than show and describe ultimate principle of the present invention, principal character and advantage.The technician of the industry should understand, and above-described embodiment does not limit the present invention in any form, the technical scheme that the mode that all employings are equal to replacement or equivalent transformation obtains, and all drops in protection scope of the present invention.
Claims (10)
1. how appropriate pyrrole smooth an intermediate 2-(3,5-two-trifluoromethyl-phenyl) synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, comprise the following steps:
，
With such as formula two (trifluoromethyl) bromobenzene of the compound 3.5-shown in II for raw material, deposit at the first alkali reagent and in the first solvent, react 1-24h with diethyl malonate in case, temperature of reaction be 0 DEG C to the first solvent reflux temperature, generate such as formula the compound one shown in III, then by compound one in the second solvent, saponification is carried out by the second alkali reagent, decarboxylic reaction 1-24h generates such as formula the compound two shown in IV, temperature of reaction is room temperature to the second solvent reflux temperature, finally compound two is deposited at the 3rd alkali reagent and in the 3rd solvent, react 1-24h with methylating reagent in case, temperature of reaction be-5 DEG C to the 3rd solvent reflux temperature, obtain such as formula the 2-(3 shown in I, 5-pair-trifluoromethyl-phenyl)-2-rnethyl-propanoic acid.
2. the smooth intermediate 2-(3 of the how appropriate pyrrole of one according to claim 1,5-is two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, the first described alkali reagent is sodium hydride, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, any one in sodium ethylate.
3. the smooth intermediate 2-(3 of the how appropriate pyrrole of one according to claim 1 and 2,5-is two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, the amount of substance of the first described alkali reagent and two (trifluoromethyl) bromobenzene of 3.5-is than being (1-2): 1, and the amount of substance of described diethyl malonate and two (trifluoromethyl) bromobenzene of 3.5-is than being (1-2): 1.
4. the smooth intermediate 2-(3 of the how appropriate pyrrole of one according to claim 1,5-is two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, the first described solvent is dimethyl sulfoxide (DMSO), N, any one in dinethylformamide, Isosorbide-5-Nitrae-dioxane, toluene, dimethylbenzene.
5. the smooth intermediate 2-(3 of the how appropriate pyrrole of one according to claim 1,5-is two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, the second described alkali reagent is any one in lithium hydroxide, sodium hydroxide, potassium hydroxide, and the second described alkali reagent is (1-5) with the amount of substance ratio of compound one: 1.
6. the smooth intermediate 2-(3 of the how appropriate pyrrole of one according to claim 1,5-is two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, the second described solvent is any one in methylene dichloride, toluene, acetonitrile, water, tetrahydrofuran (THF), methyl alcohol, ethanol, propyl carbinol.
7. the smooth intermediate 2-(3 of the how appropriate pyrrole of one according to claim 1,5-is two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, the 3rd described alkali reagent is sodium hydride, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, any one in sodium ethylate.
8. the smooth intermediate 2-(3 of the how appropriate pyrrole of the one according to claim 1 or 8,5-is two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, the 3rd described alkali reagent is (1-4) with the ratio of the amount of substance of compound two: 1, and described methylating reagent is (1-3.5) with the ratio of the amount of substance of compound two: 1.
9. the smooth intermediate 2-(3 of the how appropriate pyrrole of one according to claim 1,5-is two-trifluoromethyl-phenyl) and the synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, the 3rd described solvent is dimethyl sulfoxide (DMSO), N, any one in dinethylformamide, Isosorbide-5-Nitrae-dioxane, toluene, dimethylbenzene, acetonitrile, tetrahydrofuran (THF).
10. the how appropriate pyrrole of one according to claim 1 smooth intermediate 2-(3,5-two-trifluoromethyl-phenyl) synthetic method of-2-rnethyl-propanoic acid, it is characterized in that, described methylating reagent is methylcarbonate or methyl-sulfate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107721815A (en) * | 2017-09-21 | 2018-02-23 | 爱斯特（成都）生物制药股份有限公司 | The preparation method of one kind 2 (3,5 2 (trifluoromethyl) phenyl) 2 methylpropanoic acids of synthesis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107721815A (en) * | 2017-09-21 | 2018-02-23 | 爱斯特（成都）生物制药股份有限公司 | The preparation method of one kind 2 (3,5 2 (trifluoromethyl) phenyl) 2 methylpropanoic acids of synthesis |
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Application publication date: 20160420 |